Obesity has reached epidemic levels worldwide and is feared to cause significant toll with its co-morbidity, especially type 2 diabetes. Pathogenesis of type 2 diabetes includes both insulin resistance and islet failure. Although several hypotheses link obesity and insulin resistance, the mechanism responsible for the development of islet failure in obesity is not well understood. Interestingly, neuropeptide Y (NPY), the peptide in the brain that is known to play a role in the development of obesity, is also found in the pancreatic islets and decreases insulin secretion. Therefore both NPY in the brain and the pancreas may contribute to islet dysfunction and potentially serves as a link between diabetes and obesity. The goal of this study is to clarify the role of NPY in the development of islet failure in type 2 diabetes. The regulation of insulin secretion by NPY in the brain and the pancreas will be studied by placing NPY deficient mice on high fat diet to induce obesity and diabetes. We will analyze whether the lack of NPY prevents the development of diet-induced diabetes and improves insulin secretion in NPY deficient mice. The role of NPY in the brain will be tested by administration of NPY to the brain and measurement of glucose stimulated insulin secretion. The inhibitory effect of pancreatic NPY will be analyzed by adding NPY to isolated islets. The study will provide a unique opportunity to test the role of NPY in islet failure and its link with obesity. In addition to deepening our knowledge of islet dysfunction in type 2 diabetes, the project will provide superb training for the principal investigator, Dr. Imai, to develop an academic career in Diabetes/ Endocrinology. The study will be carried out in the Penn Diabetes Center and the Division of Endocrinology, Diabetes, and Metabolism at the University of Pennsylvania under the supervision of Dr. Rexford Ahima and Dr. Franz Matschinsky. The division has expertise in diabetes and obesity research, and will provide an outstanding environment to conduct the proposed project.